This is the first revision of a competitive renewal application designed to expand on our current studies entitled "Aging, Macrophage Mediators, and Burn Injury" (R01 AG18859). The overall goal of the proposed work is to determine mechanisms by which the pro-inflammatory milieu of aged mice predisposes them to elevated systemic and pulmonary inflammation after burn injury. Even in the absence of injury, healthy aged subjects have an elevated basal inflammatory state. This age-dependent phenomenon, referred to as inflamm-aging, renders the elderly more susceptible than young to traumatic injury, such as burn. The lung is a critical organ, which is particularly sensitive to remote injury and the resultant inflammatory sequelae. This is, in part, by virtue of its massive vascular bed and delicate alveolar architecture. Because of this, it is well established that acute lung injury, which occurs frequently after remote tissue damage, such as burn, plays a role in the poor prognosis seen in aged injured patients. Using a murine model of dorsal scald injury, we previously reported that after injury aged mice 1) are less likely to survive and 2) have significantly elevated circulating levels of IL-6 when compared to burn-injured young mice. Additional new preliminary data show that 1) in the absence of injury, the lungs of aged mice have an elevated basal level of inflammation relative to young, and 2) the combination of age and injury act exacerbates pulmonary inflammatory responses. From these pieces of evidence, we hypothesize that the elevated pro-inflammatory milieu of the aged predisposes them to increased pulmonary pathology and a poor prognosis after burn injury. Moreover, this enhanced inflammatory state is due to the influence of both intrinsic and extrinsic factors on macrophage function, including an alteration in the profile of cytokines that they produce. To test this hypothesis, we will first determine if, relative to young, aged burn-injured mice have 1) a more severe or prolonged systemic or pulmonary inflammatory response, and 2) increased pulmonary production of pro-inflammatory cytokines (IL-6 and TNFa) and chemokines (MIP-2 and MCP-1). Next, we will determine if macrophages are responsible for the heightened pro-inflammatory milieu in aged-injured mice using in vitro cell culture experiments and in vivo adoptive transfer studies. Finally, we will determine if the effects of injury on pulmonary inflammation can be ameliorated by performing studies using aged IL-6 deficient mice, or aged wild type mice given anti-IL-6 antibody or estrogen. Together these studies will provide new insights into the role of macrophages in inflamm-aging and may help determine whether different treatment strategies should be considered for young and aged burn patients.